Impaired Sarcoplasmic Reticulum Calcium Uptake and Release Promote Electromechanically and Spatially Discordant Alternans: A Computational Study

Abstract

Cardiac electrical dynamics are governed by cellular-level properties, such as action potential duration (APD) restitution and intracellular calcium (Ca) handling, and tissue-level properties, including conduction velocity restitution and cell–cell coupling. Irregular dynamics at the cellular level can lead to instabilities in cardiac tissue, including alternans, a beat-to-beat alternation in the action potential and/or the intracellular Ca transient. In this study, we incorporate a detailed single cell coupled map model of Ca cycling and bidirectional APD-Ca coupling into a spatially extended tissue model to investigate the influence of sarcoplasmic reticulum (SR) Ca uptake and release properties on alternans and conduction block. We find that an intermediate SR Ca uptake rate and larger SR Ca release resulted in the widest range of stimulus periods that promoted alternans. However, both reduced SR Ca uptake and release promote arrhythmogenic spatially and electromechanically discordant alternans, suggesting a complex interaction between SR Ca handling and alternans characteristics at the cellular and tissue level.

Exploring Impaired SERCA Pump-Caused Alternation Occurrence in Ischemia

“…However, the slight fluctuations of Ca sr alone are insufficient to maintain Ca 2+ alternans without the steep slope of Ca 2+ release curve. The large fraction of Ca 2+ release is demonstrated to generate Ca 2+ alternans [16, 23, 25, 39]. Figure 2 shows that the curve slopes change slightly before the onset of alternans in different ischemic conditions.…”

“…Our results show that large β can be induced by the impaired SERCA pump. This can be easily understood through introducing a Ca 2+ cycling hypothesis [16]: cytosolic Ca 2+ , taken up by the SERCA pump in the NSR, is released by the RyRs channels in the JSR. Thus, the process of transporting Ca 2+ from the NSR to the JSR results in a delayed Ca 2+ release after the uptake.…”

“…Furthermore, the steep slope of the curve is also able to explain the impaired SERCA pump-caused Ca 2+ alternans [19]. The onset of Ca 2+ alternans in HF and in this study can be described as follows [9, 16]: when the slope of the curve is steep at certain Ca sr , a small increment of diastolic Ca sr will result in a larger Ca 2+ release, where released Ca 2+ cannot be completely refilled back to the SR by impaired SERCA pumps. In the following heartbeat, the decreased Ca sr gives rise to a smaller subsequent Ca 2+ release.…”

“…Alternans depends on instabilities of membrane voltage ( V m ) [13] or/and intracellular Ca 2+ handling [1, 7, 9, 14–20], due to their bidirectional couplings [3, 9, 21]. For the latter, it is known that the Ca 2+ handling includes Ca 2+ influx and efflux [16], and its abnormality can arise from the dysfunction of sarcoplasmic reticulum (SR) calcium transport ATPase (SERCA) [11, 13, 14], ryanodine receptor (RyR2) [1, 4, 7, 14, 16], and Ca 2+ leak [13]. Under ischemic conditions, both the Ca 2+ release current ( I rel ) [4] and the Ca 2+ uptake current ( I up ) decrease [4, 22] to facilitate the formation of Ca 2+ alternans in an interactive manner.…”

Calcium Dynamics and Cardiac Arrhythmia

“…The article by Weinberg 8 is a computational study integrating electrical and calcium dynamics into a model of cardiac tissue to study the irregular rhythm known as alternans, a beat-to-beat alternation in the action potential, and/or intracellular calcium transient. The alternation of the action potential and the calcium transient can be in-phase or out-of-phase, both within the same cell or throughout the tissue.…”